The studies in this application propose to develop a simple oral glucose tolerance test (OGTT) as a tool to enhance the utility of plasma amyloid-beta (A[unreadable]) as a biomarker of Alzheimer's disease (AD). Currently, there are many on-going clinical trials for potential treatment of AD. Therefore, it is important to be able to identify AD patients in the earlier stages who would be ideal candidates for these therapies. Plasma A[unreadable] would be an inexpensive and non-invasive tool in diagnosing various stages of AD, as well as for monitoring A[unreadable] modifying therapies. However, most cross-sectional studies involving plasma A[unreadable] have not been able to show differences between individuals with AD compared to controls. In our project, we propose to "unmask" the differences between individuals who have normal cognition, mild cognitive impairment (MCI), and early AD (AD) by modulating the plasma A[unreadable] levels with OGTT. We also propose to demonstrate that this effect may be due to lower glucagon-like peptide-1 (GLP-1) release in response to OGTT. In a cross-sectional study, we will administer OGTT to a group of individuals in each of the amnestic MCI (aMCI), AD and cognitively normal control groups. Plasma samples will be obtained at various time points and quantified for A[unreadable] 42 and GLP-1 by ELISA. Then, we will compare at a single time point, the area under curve (AUC) of A[unreadable] 42 kinetics in response to OGTT across the three groups, and also correlate it to the performance on tests of memory. We will also compare the AUC of plasma GLP-1 kinetics in response to OGTT, and correlate to the AUC of plasma A[unreadable] 42 kinetics. The results of this exploratory study will provide data regarding the potential utility of OGTT modulated plasma A[unreadable] 42 as a diagnostic biomarker of MCI and AD, as well as a biomarker of disease severity. It will also provide data on the potential relationship between GLP-1 to plasma A[unreadable] 42 levels in response to OGTT. In addition, the data from this exploratory study will enable us to gather sufficient data to design a longitudinal study to demonstrate the utility of OGTT in differentiating subjects, monitor therapeutic response and predict disease progression. PUBLIC HEALTH RELEVANCE: The studies in this application propose to develop a simple oral glucose tolerance test as a tool to meaningfully assess plasma amyloid levels. As the incidence of Alzheimer's disease (AD) climbs and the biological and cognitive ramifications of such a disorder become more debilitating, the importance of early intervention is tremendous. Development of a reliable biomarker that is simple and non-invasive would enable early identification of individuals who are at risk for AD, and may allow earlier treatment.